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1.
Nutrients ; 13(7)2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34371846

RESUMO

Aside from its role in bone metabolism, vitamin D is a key immunomodulatory micronutrient. The active form of vitamin D (1,25(OH)D) seems to modulate the innate immune system through different mechanisms. The vitamin is involved in the differentiation of monocytes into macrophages, increasing the phagocytic and chemotactic functions of these cells. At the same time, vitamin D enables efferocytosis and prevents immunopathology. In addition, vitamin D is involved in other processes related to immune function, such as inflammation. Regarding muscle tissue, vitamin D plays an active role in muscle inflammatory response, protein synthesis, and regulation of skeletal muscle function. Two mechanisms have been proposed: A direct role of 1,25(OH)D binding to vitamin D receptors (VDRs) in muscle cells and the modulation of calcium transport in the sarcoplasmic reticulum. This second mechanism needs additional investigation. In conclusion, vitamin D seems to be effective in cases of deficiency and/or if there is a great muscular commitment, such as in high intensity exercises.


Assuntos
Imunomodulação/efeitos dos fármacos , Músculo Esquelético/imunologia , Doenças Musculares/imunologia , Vitamina D/farmacologia , Diferenciação Celular/efeitos dos fármacos , Exercício Físico/fisiologia , Treinamento Intervalado de Alta Intensidade/efeitos adversos , Humanos , Inflamação , Macrófagos/efeitos dos fármacos , Monócitos/efeitos dos fármacos , Doenças Musculares/etiologia , Receptores de Calcitriol/imunologia
2.
Molecules ; 26(16)2021 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-34443554

RESUMO

Rheumatoid arthritis (RA) is an autoimmune inflammatory joint disease with complex pathogenesis associated with cytokine dysregulation. Macrophage migration inhibitory factor (MIF) plays a role in systemic inflammation and joint destruction in RA and could be associated with the secretion of other immune-modulatory cytokines such as IL-25, IL-31, and IL-33. For the above, our main aim was to evaluate the IL-25, IL-31, and IL-33 secretion from recombinant human MIF (rhMIF)-stimulated peripheral blood mononuclear cells (PBMC) of RA patients. The rhMIF and lipopolysaccharide (LPS) plus rhMIF stimuli promote the secretion of IL-25, IL-31, and IL-33 (p < 0.05) from PBMC of RA patients. The study groups, the different stimuli, and the interaction between both showed a statistically significant effect on the secretion of IL-25 (p < 0.05) and IL-31 (p < 0.01). The study of the effect of the RA patient treatments and their interaction with the effect of stimuli did not show an interaction between them. In conclusion, our study generates new evidence for the role of MIF in the secretion of IL-25, IL-31, and IL-33 and its immunomodulatory effect on RA.


Assuntos
Artrite Reumatoide/imunologia , Artrite Reumatoide/metabolismo , Interleucina-17/metabolismo , Interleucina-33/metabolismo , Interleucinas/metabolismo , Oxirredutases Intramoleculares/metabolismo , Leucócitos Mononucleares/metabolismo , Fatores Inibidores da Migração de Macrófagos/metabolismo , Adulto , Feminino , Humanos , Imunomodulação/efeitos dos fármacos , Oxirredutases Intramoleculares/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/imunologia , Fatores Inibidores da Migração de Macrófagos/farmacologia , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes/farmacologia
3.
Nutrients ; 13(7)2021 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-34371830

RESUMO

Nutrition can modulate host immune responses as well as promote anticancer effects. In this study, two nutritional supplements, namely gamma-tocotrienol (γT3) and Spirulina, were evaluated for their immune-enhancing and anticancer effects in a syngeneic mouse model of breast cancer (BC). Five-week-old female BALB/c mice were fed Spirulina, γT3, or a combination of Spirulina and γT3 (Spirulina + γT3) for 56 days. The mice were inoculated with 4T1 cells into their mammary fat pad on day 28 to induce BC. The animals were culled on day 56 for various analyses. A significant reduction (p < 0.05) in tumor volume was only observed on day 37 and 49 in animals fed with the combination of γT3 + Spirulina. There was a marked increase (p < 0.05) of CD4/CD127+ T-cells and decrease (p < 0.05) of T-regulatory cells in peripheral blood from mice fed with either γT3 or Spirulina. The breast tissue of the combined group showed abundant areas of necrosis, but did not prevent metastasis to the liver. Although there was a significant increase (p < 0.05) of MIG-6 and Cadherin 13 expression in tumors from γT3-fed animals, there were no significant (p > 0.05) differences in the expression of MIG-6, Cadherin 13, BIRC5, and Serpine1 upon combined feeding. This showed that combined γT3 + Spirulina treatment did not show any synergistic anticancer effects in this study model.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/terapia , Suplementos Nutricionais , Imunomodulação/efeitos dos fármacos , Spirulina , Animais , Cromanos , Modelos Animais de Doenças , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Vitamina E/análogos & derivados
4.
Molecules ; 26(11)2021 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-34200163

RESUMO

Tea polysaccharides (TPSs) are one of the main bioactive constituents of tea with various biological activities such as hypoglycemic effect, antioxidant, antitumor, and immunomodulatory. The bioactivities of TPSs are directly associated with their structures such as chemical composition, molecular weight, glycosidic linkages, and conformation among others. To study the relationship between the structures of TPSs and their bioactivities, it is essential to elucidate the structure of TPSs, particularly the fine structures. Due to the vast variation nature of monosaccharide units and their connections, the structure of TPSs is extremely complex, which is also affected by several major factors including tea species, processing technologies of tea and isolation methods of TPSs. As a result of the complexity, there are few studies on their fine structures and chain conformation. In the present review, we aim to provide a detailed summary of the multiple factors influencing the characteristics of TPS chemical structures such as variations of tea species, degree of fermentation, and preparation methods among others as well as their applications. The main aspects of understanding the structural difference of TPSs and influencing factors are to assist the study of the structure and bioactivity relationship and ultimately, to control the production of the targeted TPSs with the most desired biological activity.


Assuntos
Polissacarídeos/química , Chá/química , Antioxidantes/química , Fermentação/fisiologia , Imunomodulação/efeitos dos fármacos , Monossacarídeos/química
5.
Int J Mol Sci ; 22(12)2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34203758

RESUMO

Synovial fluid contains cytokines, growth factors and resident mesenchymal stem cells (MSCs). The present study aimed to (1) determine the effects of autologous and allogeneic synovial fluid on viability, proliferation and chondrogenesis of equine bone marrow MSCs (BMMSCs) and (2) compare the immunomodulatory properties of equine synovial fluid MSCs (SFMSCs) and BMMSCs after stimulation with interferon gamma (INF-γ). To meet the first aim of the study, the proliferation and viability of MSCs were evaluated by MTS and calcein AM staining assays. To induce chondrogenesis, MSCs were cultured in a medium containing TGF-ß1 or different concentrations of synovial fluid. To meet the second aim, SFMSCs and BMMSCs were stimulated with IFN-γ. The concentration of indoleamine-2,3-dioxygenase (IDO) and nitric oxide (NO) were examined. Our results show that MSCs cultured in autologous or allogeneic synovial fluid could maintain proliferation and viability activities. Synovial fluid affected chondrocyte differentiation significantly, as indicated by increased glycosaminoglycan contents, compared to the chondrogenic medium containing 5 ng/mL TGF-ß1. After culturing with IFN-γ, the conditioned media of both BMMSCs and SFMSCs showed increased concentrations of IDO, but not NO. Stimulating MSCs with synovial fluid or IFN-γ could enhance chondrogenesis and anti-inflammatory activity, respectively, suggesting that the joint environment is suitable for chondrogenesis.


Assuntos
Condrogênese/efeitos dos fármacos , Imunomodulação/efeitos dos fármacos , Interferon gama/farmacologia , Células-Tronco Mesenquimais/imunologia , Líquido Sinovial/metabolismo , Animais , Células da Medula Óssea/citologia , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Forma Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaio de Unidades Formadoras de Colônias , Cavalos , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/enzimologia , Óxido Nítrico/metabolismo
6.
Molecules ; 26(12)2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34203809

RESUMO

Rhododendron (Ericaceae) extracts contain flavonoids, chromones, terpenoids, steroids, and essential oils and are used in traditional ethnobotanical medicine. However, little is known about the immunomodulatory activity of essential oils isolated from these plants. Thus, we isolated essential oils from the flowers and leaves of R. albiflorum (cascade azalea) and analyzed their chemical composition and innate immunomodulatory activity. Compositional analysis of flower (REOFl) versus leaf (REOLv) essential oils revealed significant differences. REOFl was comprised mainly of monoterpenes (92%), whereas sesquiterpenes were found in relatively low amounts. In contrast, REOLv was primarily composed of sesquiterpenes (90.9%), with a small number of monoterpenes. REOLv and its primary sesquiterpenes (viridiflorol, spathulenol, curzerene, and germacrone) induced intracellular Ca2+ mobilization in human neutrophils, C20 microglial cells, and HL60 cells transfected with N-formyl peptide receptor 1 (FPR1) or FPR2. On the other hand, pretreatment with these essential oils or component compounds inhibited agonist-induced Ca2+ mobilization and chemotaxis in human neutrophils and agonist-induced Ca2+ mobilization in microglial cells and FPR-transfected HL60 cells, indicating that the direct effect of these compounds on [Ca2+]i desensitized the cells to subsequent agonist activation. Reverse pharmacophore mapping suggested several potential kinase targets for these compounds; however, these targets were not supported by kinase binding assays. Our results provide a cellular and molecular basis to explain at least part of the beneficial immunotherapeutic properties of the R. albiflorum essential oils and suggest that essential oils from leaves of this plant may be effective in modulating some innate immune responses, possibly by inhibition of neutrophil migration.


Assuntos
Óleos Voláteis/química , Rhododendron/química , Flores/química , Células HL-60 , Humanos , Fatores Imunológicos/isolamento & purificação , Fatores Imunológicos/metabolismo , Imunomodulação/efeitos dos fármacos , Monoterpenos/farmacologia , Neutrófilos/efeitos dos fármacos , Óleos Voláteis/farmacologia , Folhas de Planta/química , Receptores de Formil Peptídeo/efeitos dos fármacos , Receptores de Formil Peptídeo/metabolismo , Rhododendron/metabolismo , Sesquiterpenos/farmacologia
7.
Int J Mol Sci ; 22(13)2021 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-34199099

RESUMO

Eltrombopag is a thrombopoietin receptor (MPL) agonist approved for the treatment of primary immune thrombocytopenia (ITP). Recent evidence shows that some patients may sustain platelet counts following eltrombopag discontinuation. The systemic immunomodulatory response that resolves ITP in some patients could result from an increase in platelet mass, caused either by the direct action of eltrombopag on megakaryocytes through MPL stimulation, or potential MPL-independent actions on other cell types. To uncover the possible mechanisms of action of eltrombopag, in silico analyses were performed, including a systems biology-based approach, a therapeutic performance mapping system, and structural analyses. Through manual curation of the available bibliography, 56 key proteins were identified and integrated into the ITP interactome analysis. Mathematical models (94.92% mean accuracy) were obtained to elucidate potential MPL-dependent pathways in non-megakaryocytic cell subtypes. In addition to the effects on megakaryocytes and platelet numbers, the results were consistent with MPL-mediated effects on other cells, which could involve interferon-gamma, transforming growth factor-beta, peroxisome proliferator-activated receptor-gamma, and forkhead box protein P3 pathways. Structural analyses indicated that effects on three apoptosis-related proteins (BCL2L1, BCL2, BAX) from the Bcl-2 family may be off-target effects of eltrombopag. In conclusion, this study proposes new hypotheses regarding the immunomodulatory functions of eltrombopag in patients with ITP.


Assuntos
Benzoatos/farmacologia , Hidrazinas/farmacologia , Imunomodulação/efeitos dos fármacos , Púrpura Trombocitopênica Idiopática/etiologia , Púrpura Trombocitopênica Idiopática/metabolismo , Pirazóis/farmacologia , Receptores de Trombopoetina/antagonistas & inibidores , Benzoatos/química , Benzoatos/uso terapêutico , Biomarcadores , Gerenciamento Clínico , Suscetibilidade a Doenças , Humanos , Hidrazinas/química , Hidrazinas/uso terapêutico , Modelos Biológicos , Modelos Moleculares , Terapia de Alvo Molecular/métodos , Mapeamento de Interação de Proteínas , Mapas de Interação de Proteínas , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Pirazóis/química , Pirazóis/uso terapêutico , Receptores de Trombopoetina/química , Receptores de Trombopoetina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Resultado do Tratamento
8.
Nat Commun ; 12(1): 4447, 2021 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-34290243

RESUMO

Tryptophan catabolism is a major metabolic pathway utilized by several professional and non-professional antigen presenting cells to maintain immunological tolerance. Here we report that 3-hydroxy-L-kynurenamine (3-HKA) is a biogenic amine produced via an alternative pathway of tryptophan metabolism. In vitro, 3-HKA has an anti-inflammatory profile by inhibiting the IFN-γ mediated STAT1/NF-κΒ pathway in both mouse and human dendritic cells (DCs) with a consequent decrease in the release of pro-inflammatory chemokines and cytokines, most notably TNF, IL-6, and IL12p70. 3-HKA has protective effects in an experimental mouse model of psoriasis by decreasing skin thickness, erythema, scaling and fissuring, reducing TNF, IL-1ß, IFN-γ, and IL-17 production, and inhibiting generation of effector CD8+ T cells. Similarly, in a mouse model of nephrotoxic nephritis, besides reducing inflammatory cytokines, 3-HKA improves proteinuria and serum urea nitrogen, overall ameliorating immune-mediated glomerulonephritis and renal dysfunction. Overall, we propose that this biogenic amine is a crucial component of tryptophan-mediated immune tolerance.


Assuntos
Aminas Biogênicas/farmacologia , Imunomodulação/efeitos dos fármacos , Cinurenina/análogos & derivados , Animais , Aminas Biogênicas/metabolismo , Aminas Biogênicas/uso terapêutico , Linhagem Celular Tumoral , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Modelos Animais de Doenças , Células Endoteliais , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Indolamina-Pirrol 2,3,-Dioxigenase/imunologia , Inflamação , Interferon gama/farmacologia , Cinurenina/metabolismo , Cinurenina/farmacologia , Cinurenina/uso terapêutico , Camundongos , NF-kappa B/metabolismo , Nefrite/tratamento farmacológico , Nefrite/imunologia , Psoríase/tratamento farmacológico , Psoríase/imunologia , Triptofano/metabolismo
9.
Int J Mol Sci ; 22(13)2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34202218

RESUMO

Periprosthetic joint infections (PJIs) caused by Staphylococcus aureus infection are difficult to treat due to antibiotic resistance. It is known that the biofilms from methicillin-resistant S. aureus (MRSA) promote expansion of myeloid-derived suppressor cells (MDSCs) to suppress T-cell proliferation and benefit bacterial infections. This study finds that GMI, a fungal immunomodulatory peptide isolated from Ganoderma microsporum, suppresses MDSC expansion to promote the proliferation of cytotoxic T cells. The enhancement is likely attributed to increased expression of IL-6 and TNF-α and reduction in ROS expression. Similar beneficial effects of GMI on the suppression of MDSC expansion and IL-6 expression are also observed in the whole blood and reduces the accumulation of MDSCs in the infected bone region in a mouse PJI infection model. This study shows that GMI is potentially useful for treating S. aureus-induced PJIs.


Assuntos
Ganoderma/química , Imunomodulação/efeitos dos fármacos , Células Supressoras Mieloides/efeitos dos fármacos , Células Supressoras Mieloides/imunologia , Peptídeos/farmacologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Animais , Artrite Infecciosa/diagnóstico , Artrite Infecciosa/tratamento farmacológico , Artrite Infecciosa/etiologia , Artrite Infecciosa/metabolismo , Biofilmes/efeitos dos fármacos , Biomarcadores , Biópsia , Citocinas/metabolismo , Modelos Animais de Doenças , Suscetibilidade a Doenças , Masculino , Camundongos , Células Supressoras Mieloides/metabolismo , Peptídeos/química , Infecções Relacionadas à Prótese/diagnóstico , Infecções Relacionadas à Prótese/tratamento farmacológico , Infecções Relacionadas à Prótese/etiologia , Infecções Relacionadas à Prótese/metabolismo , Espécies Reativas de Oxigênio , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/fisiologia , Linfócitos T/metabolismo
10.
J Photochem Photobiol B ; 221: 112247, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34175580

RESUMO

A need exists for further research elucidating the benefits of environmentally safe photoprotective agents against ultraviolet (UV) exposure, and plant extracts represent a human-friendly alternative formulation. This study was designed to evaluate the potential use of Bellis perennis extract (BPE), from the Asteraceae family, known as the common daisy or the English daisy, in cosmeceuticals as a photoprotective factor, using an in vitro model of UVA-induced keratinocyte damage. Human skin keratinocytes (HaCaT cell line) were incubated with BPE at 0.01, 0.1, or 1% in Dulbecco's Modified Eagle Medium (DMEM), and after 15 min they were submitted to UVA radiation at 5, 10, and 15 J/cm2 doses, respectively. For comparative purposes, Polypodium leucotomos extract (PLE), known as the fern, was used as a positive control in assessing the photoprotective effect. After 24 h of UVA exposure, cell viability (MTT and LDH assays), levels of cleaved caspase-3, cyclooxygenase-2, IL-6, reactive oxygen species (ROS) and antioxidant enzyme (catalase, SOD, and glutathione peroxidase) activity were determined. UVA radiation at 5, 10, and 15 J/cm2 doses reduced cell viability to 63%, 43%, and 23%, respectively; we selected 10 J/cm2 for our purposes. After 24 h of UVA exposure, treatment with 1% BPE and 1% PLE significantly recovered cell viability (p < 0.05). Furthermore, treatment was associated with lower cleaved caspase-3 and ROS levels, higher catalase activity, and lower IL-6 levels in the treated UVA keratinocytes compared with the untreated UVA group (p < 0.01). Our results demonstrate photoprotective and immunomodulatory effects of BPE in skin keratinocytes and support its use as a bioactive agent in cosmetic formulations to prevent skin damage caused by exposure to the UV light.


Assuntos
Asteraceae/química , Imunomodulação/efeitos dos fármacos , Extratos Vegetais/farmacologia , Protetores contra Radiação/farmacologia , Raios Ultravioleta , Asteraceae/metabolismo , Caspase 3/metabolismo , Catalase/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Humanos , Imunomodulação/efeitos da radiação , Queratinócitos/citologia , Queratinócitos/metabolismo , Extratos Vegetais/química , Protetores contra Radiação/química , Espécies Reativas de Oxigênio/metabolismo
11.
Nutrients ; 13(6)2021 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-34073784

RESUMO

Mounting evidence support the potential benefits of functional foods or nutraceuticals for human health and diseases. Black cumin (Nigella sativa L.), a highly valued nutraceutical herb with a wide array of health benefits, has attracted growing interest from health-conscious individuals, the scientific community, and pharmaceutical industries. The pleiotropic pharmacological effects of black cumin, and its main bioactive component thymoquinone (TQ), have been manifested by their ability to attenuate oxidative stress and inflammation, and to promote immunity, cell survival, and energy metabolism, which underlie diverse health benefits, including protection against metabolic, cardiovascular, digestive, hepatic, renal, respiratory, reproductive, and neurological disorders, cancer, and so on. Furthermore, black cumin acts as an antidote, mitigating various toxicities and drug-induced side effects. Despite significant advances in pharmacological benefits, this miracle herb and its active components are still far from their clinical application. This review begins with highlighting the research trends in black cumin and revisiting phytochemical profiles. Subsequently, pharmacological attributes and health benefits of black cumin and TQ are critically reviewed. We overview molecular pharmacology to gain insight into the underlying mechanism of health benefits. Issues related to pharmacokinetic herb-drug interactions, drug delivery, and safety are also addressed. Identifying knowledge gaps, our current effort will direct future research to advance potential applications of black cumin and TQ in health and diseases.


Assuntos
Nigella sativa/química , Preparações de Plantas/química , Preparações de Plantas/farmacologia , Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacocinética , Antioxidantes/farmacologia , Benzoquinonas/análise , Disponibilidade Biológica , Sobrevivência Celular/efeitos dos fármacos , Suplementos Nutricionais , Sistemas de Liberação de Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Metabolismo Energético , Alimento Funcional , Humanos , Imunomodulação/efeitos dos fármacos , Inflamação/terapia , Estresse Oxidativo/efeitos dos fármacos , Fitoterapia/métodos , Preparações de Plantas/farmacocinética
12.
Molecules ; 26(9)2021 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-34063301

RESUMO

Amomum Villosum Lour. (A. villosum) is a folk medicine that has been used for more than 1300 years. However, study of the polysaccharides of A. villosum is seriously neglected. The objectives of this study are to explore the structural characteristics of polysaccharides from A. villosum (AVPs) and their effects on immune cells. In this study, the acidic polysaccharides (AVPG-1 and AVPG-2) were isolated from AVPs and purified via anion exchange and gel filtration chromatography. The structural characteristics of the polysaccharides were characterized by methylation, HPSEC-MALLS-RID, HPLC, FT-IR, SEM, GC-MS and NMR techniques. AVPG-1 with a molecular weight of 514 kDa had the backbone of → 4)-α-d-Glcp-(1 → 3,4)-ß-d-Glcp-(1 → 4)-α-d-Glcp-(1 →. AVPG-2 with a higher molecular weight (14800 kDa) comprised a backbone of → 4)-α-d-Glcp-(1 → 3,6)-ß-d-Galp-(1 → 4)-α-d-Glcp-(1 →. RAW 264.7 cells were used to investigate the potential effect of AVPG-1 and AVPG-2 on macrophages, and lipopolysaccharide (LPS) was used as a positive control. The results from bioassays showed that AVPG-2 exhibited stronger immunomodulatory activity than AVPG-1. AVPG-2 significantly induced nitric oxide (NO) production as well as the release of interleukin (IL)-6 and tumor necrosis factor alpha (TNF-α), and upregulated phagocytic capacities of RAW 264.7 cells. Real-time PCR analysis revealed that AVPG-2 was able to turn the polarization of macrophages to the M1 direction. These results suggested that AVPs could be explored as potential immunomodulatory agents of the functional foods or complementary medicine.


Assuntos
Amomum/química , Polissacarídeos/química , Polissacarídeos/metabolismo , Animais , Sobrevivência Celular , Cromatografia Líquida de Alta Pressão , Citocinas/metabolismo , Etanol , Fatores Imunológicos , Imunomodulação/efeitos dos fármacos , Lipopolissacarídeos/química , Macrófagos/metabolismo , Espectroscopia de Ressonância Magnética , Camundongos , Microscopia Eletrônica de Varredura , Peso Molecular , Óxido Nítrico/química , Fagocitose , Células RAW 264.7 , Espectroscopia de Infravermelho com Transformada de Fourier , Propriedades de Superfície
13.
Nat Commun ; 12(1): 3611, 2021 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-34127673

RESUMO

Yeast is an integral part of mammalian microbiome, and like commensal bacteria, has the potential of being harnessed to influence immunity in clinical settings. However, functional specificities of yeast-derived immunoregulatory molecules remain elusive. Here we find that while under steady state, ß-1,3-glucan-containing polysaccharides potentiate pro-inflammatory properties, a relatively less abundant class of cell surface polysaccharides, dubbed mannan/ß-1,6-glucan-containing polysaccharides (MGCP), is capable of exerting potent anti-inflammatory effects to the immune system. MGCP, in contrast to previously identified microbial cell surface polysaccharides, through a Dectin1-Cox2 signaling axis in dendritic cells, facilitates regulatory T (Treg) cell induction from naïve T cells. Furthermore, through a TLR2-dependent mechanism, it restrains Th1 differentiation of effector T cells by suppressing IFN-γ expression. As a result, administration of MGCP display robust suppressive capacity towards experimental inflammatory disease models of colitis and experimental autoimmune encephalomyelitis (EAE) in mice, thereby highlighting its potential therapeutic utility against clinically relevant autoimmune diseases.


Assuntos
Imunomodulação/efeitos dos fármacos , Imunomodulação/imunologia , Polissacarídeos/imunologia , Saccharomyces cerevisiae/metabolismo , beta-Glucanas/imunologia , Animais , Linfócitos T CD4-Positivos , Diferenciação Celular/efeitos dos fármacos , Colite/imunologia , Colite/patologia , Ciclo-Oxigenase 2 , Células Dendríticas/imunologia , Encefalomielite Autoimune Experimental , Glucanos , Proteínas de Homeodomínio/genética , Imunidade , Lectinas Tipo C , Mananas , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Polissacarídeos/metabolismo , Polissacarídeos/farmacologia , Saccharomyces cerevisiae/genética , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Células Th1 , Zimosan , beta-Glucanas/metabolismo , beta-Glucanas/farmacologia
14.
Int J Biol Macromol ; 184: 483-496, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-34166694

RESUMO

Cyclophosphamide (CTX) was used to establish the immunosuppressive mice model. The immune organ viscera index, phagocytes vitality, the levels of cytokines in serum, the oxidative stress resistance, proteomics and intestinal flora in mice were investigated to evaluate the effect of immune regulation of Nigella sativa seed polysaccharide (NSSP). The results showed that the high-dose NSSP group could significantly increase the thymus and spleen index. The levels of ACP, LDH, T-AOC, SOD, IL-2, IL-4 and IL-6 were significantly increased and the levels of TNF-α and MDA were reduced. All evidences indicated that NSSP could improve the immune effects of the immunosuppressed mice. Proteomics investigation showed that NSSP could improve the immune by regulating the differential proteins of PI3K and PTEN, and regulating the metabolism-related pathways such as autoimmune diseases and PI3K-Akt signaling pathway. of Gut microbes analysis showed that NSSP could exert immunomodulatory effects by improving the structure of the intestinal flora, increasing the diversity of the flora, and regulating metabolic pathways such as lipid metabolism, polysaccharide synthesis and signal transduction by the prediction of flora metabolic functions. In addition, NSSP could regulate intestinal environment by regulating the content of short chain fatty acids.


Assuntos
Bactérias/classificação , Ciclofosfamida/efeitos adversos , Imunomodulação/efeitos dos fármacos , Nigella sativa/química , Polissacarídeos/administração & dosagem , Proteômica/métodos , Animais , Bactérias/efeitos dos fármacos , Bactérias/genética , Bactérias/isolamento & purificação , Citocinas/sangue , DNA Bacteriano/genética , Modelos Animais de Doenças , Ácidos Graxos Voláteis/metabolismo , Microbioma Gastrointestinal/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Redes e Vias Metabólicas , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Filogenia , Extratos Vegetais/administração & dosagem , Polissacarídeos/farmacologia , Sementes/química , Análise de Sequência de DNA
15.
Int J Mol Sci ; 22(9)2021 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-34068701

RESUMO

In addition to its canonical functions, vitamin D has been proposed to be an important mediator of the immune system. Despite ample sunshine, vitamin D deficiency is prevalent (>80%) in the Middle East, resulting in a high rate of supplementation. However, the underlying molecular mechanisms of the specific regimen prescribed and the potential factors affecting an individual's response to vitamin D supplementation are not well characterized. Our objective is to describe the changes in the blood transcriptome and explore the potential mechanisms associated with vitamin D3 supplementation in one hundred vitamin D-deficient women who were given a weekly oral dose (50,000 IU) of vitamin D3 for three months. A high-throughput targeted PCR, composed of 264 genes representing the important blood transcriptomic fingerprints of health and disease states, was performed on pre and post-supplementation blood samples to profile the molecular response to vitamin D3. We identified 54 differentially expressed genes that were strongly modulated by vitamin D3 supplementation. Network analyses showed significant changes in the immune-related pathways such as TLR4/CD14 and IFN receptors, and catabolic processes related to NF-kB, which were subsequently confirmed by gene ontology enrichment analyses. We proposed a model for vitamin D3 response based on the expression changes of molecules involved in the receptor-mediated intra-cellular signaling pathways and the ensuing predicted effects on cytokine production. Overall, vitamin D3 has a strong effect on the immune system, G-coupled protein receptor signaling, and the ubiquitin system. We highlighted the major molecular changes and biological processes induced by vitamin D3, which will help to further investigate the effectiveness of vitamin D3 supplementation among individuals in the Middle East as well as other regions.


Assuntos
Colecalciferol/genética , Imunomodulação/imunologia , Receptores de Lipopolissacarídeos/genética , Receptor 4 Toll-Like/genética , Vitamina D/genética , Adolescente , Adulto , Colecalciferol/administração & dosagem , Colecalciferol/imunologia , Suplementos Nutricionais , Feminino , Expressão Gênica/efeitos dos fármacos , Humanos , Imunomodulação/efeitos dos fármacos , Terapia Nutricional , Vitamina D/imunologia , Deficiência de Vitamina D/dietoterapia , Deficiência de Vitamina D/genética , Deficiência de Vitamina D/imunologia , Deficiência de Vitamina D/patologia , Adulto Jovem
16.
Front Immunol ; 12: 611256, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34079536

RESUMO

Ulcerative colitis (UC) is a chronic relapsing disorder of the colonic tract, characterized by a dysregulated innate and adaptive immune response to gut microbiota that contributes to the perpetuation of intestinal inflammatory processes. The Interleukin (IL) 23/IL17 axis has been reported to play a key role in UC pathogenesis promoting Th17 cells and cytokines-related immune response. Recently, the blockade of IL23/IL17 pathways has been raised enormous interest in the treatment o several chronic inflammatory disorders. In this review, we summarize the emerging results from clinical trials that evoked both promise and discouragement in IL23/IL17 axis in the treatment of UC. Targeting IL23 p40 through Ustekinumab results safe and effective to induce and maintain clinical remission, low inflammatory indexes, mucosal healing, and a better quality of life. Studies targeting IL23 p19 through Mirikizumab, Risankizumab, Brazikumab and Guselkumab are still ongoing. To date, no clinical studies targeting IL17 pathway are ongoing in UC. IL-17 targeting is thought to have a context-dependent biological effect, based on whether cytokine is selectively targeted or if its function is dampened by the upstream block of IL23.


Assuntos
Colite Ulcerativa/imunologia , Colite Ulcerativa/metabolismo , Imunomodulação/efeitos dos fármacos , Interleucina-17/metabolismo , Interleucina-23/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Colite Ulcerativa/diagnóstico , Colite Ulcerativa/tratamento farmacológico , Gerenciamento Clínico , Suscetibilidade a Doenças , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/imunologia , Humanos , Terapia de Alvo Molecular , Resultado do Tratamento , Ustekinumab/farmacologia , Ustekinumab/uso terapêutico
18.
Biomed Pharmacother ; 139: 111654, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33957563

RESUMO

Previous studies have suggested that Lycium barbarum (L. barbarum) has a radioprotective function, although more in-depth investigation is still required. We investigated the radioprotective efficacy of extract of the fruits of L. barbarum (LBE) and its radioprotective mechanisms. Mice were exposed to 8.5 Gy, 5.5 Gy, or 6.0 Gy total body irradiation (TBI), and the survival rate, lymphocyte percentage, amount of cytokines, and viability of the irradiated cells, as well as the gut microbiome and fecal metabolomics were studied. LBE enhanced the survival of the mice exposed to 8.5 Gy γ-ray TBI or 5.5 Gy X-ray TBI. After 6.0 Gy γ-ray TBI, LBE exhibited good immunomodulatory properties, mainly characterized by the accelerated recovery of lymphocyte percentages, and the enhanced expression of immune-related cytokines. LBE reconstituted the gut microbiota of irradiated mice, increased the relative abundance of potentially beneficial genera (e.g., Turicibacter, Akkermansia), and decreased the relative abundance of potentially harmful bacterial genera (e.g., Rikenellaceae_RC9_gut_group). Beneficial regulatory effects of LBE on the host metabolites were also noted, and the major upregulated metabolites induced by LBE, such as Tetrahydrofolic acid and N-ornithyl-L-taurine, were positively correlated with the immune factor interleukin (IL)-6. In vitro, LBE also increased the vitality of rat small intestinal epithelial cells (IEC-6) after 4.0 Gy γ-ray irradiation and promoted the growth of Akkermansia muciniphila. These results confirmed a radioprotective function of LBE and indicated that the radioprotective mechanism may be due to immunomodulation and the synergistically modulating effect on the gut microbiota and related metabolites.


Assuntos
Microbioma Gastrointestinal/efeitos dos fármacos , Imunidade/efeitos dos fármacos , Lycium/química , Extratos Vegetais/uso terapêutico , Lesões Experimentais por Radiação/imunologia , Lesões Experimentais por Radiação/prevenção & controle , Protetores contra Radiação/uso terapêutico , Animais , Citocinas/metabolismo , Células Epiteliais/efeitos dos fármacos , Fezes/microbiologia , Frutas/química , Imunomodulação/efeitos dos fármacos , Interleucina-6/metabolismo , Intestino Delgado/efeitos dos fármacos , Contagem de Linfócitos , Masculino , Metabolômica , Camundongos , Camundongos Endogâmicos C57BL , Lesões Experimentais por Radiação/metabolismo , Ratos , Análise de Sobrevida , Irradiação Corporal Total
19.
Nat Commun ; 12(1): 2885, 2021 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-34001887

RESUMO

Despite the widespread observations on the osteogenic effects of magnesium ion (Mg2+), the diverse roles of Mg2+ during bone healing have not been systematically dissected. Here, we reveal a previously unknown, biphasic mode of action of Mg2+ in bone repair. During the early inflammation phase, Mg2+ contributes to an upregulated expression of transient receptor potential cation channel member 7 (TRPM7), and a TRPM7-dependent influx of Mg2+ in the monocyte-macrophage lineage, resulting in the cleavage and nuclear accumulation of TRPM7-cleaved kinase fragments (M7CKs). This then triggers the phosphorylation of Histone H3 at serine 10, in a TRPM7-dependent manner at the promoters of inflammatory cytokines, leading to the formation of a pro-osteogenic immune microenvironment. In the later remodeling phase, however, the continued exposure of Mg2+ not only lead to the over-activation of NF-κB signaling in macrophages and increased number of osteoclastic-like cells but also decelerates bone maturation through the suppression of hydroxyapatite precipitation. Thus, the negative effects of Mg2+ on osteogenesis can override the initial pro-osteogenic benefits of Mg2+. Taken together, this study establishes a paradigm shift in the understanding of the diverse and multifaceted roles of Mg2+ in bone healing.


Assuntos
Regeneração Óssea/efeitos dos fármacos , Fêmur/efeitos dos fármacos , Imunomodulação/efeitos dos fármacos , Macrófagos/metabolismo , Magnésio/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Canais de Cátion TRPM/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Citocinas/imunologia , Citocinas/metabolismo , Fêmur/metabolismo , Fêmur/patologia , Expressão Gênica/efeitos dos fármacos , Humanos , Inflamação/metabolismo , Macrófagos/citologia , Macrófagos/imunologia , Magnésio/administração & dosagem , Magnésio/metabolismo , Osteoclastos/citologia , Osteoclastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Osteogênese/genética , Proteínas Serina-Treonina Quinases/genética , Ratos Sprague-Dawley , Células THP-1 , Canais de Cátion TRPM/genética
20.
Front Immunol ; 12: 617365, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33936033

RESUMO

In situ tumor ablation techniques, like radiotherapy, cryo- and heat-based thermal ablation are successfully applied in oncology for local destruction of tumor masses. Although diverse in technology and mechanism of inducing cell death, ablative techniques share one key feature: they generate tumor debris which remains in situ. This tumor debris functions as an unbiased source of tumor antigens available to the immune system and has led to the concept of in situ cancer vaccination. Most studies, however, report generally modest tumor-directed immune responses following local tumor ablation as stand-alone treatment. Tumors have evolved mechanisms to create an immunosuppressive tumor microenvironment (TME), parts of which may admix with the antigen depot. Provision of immune stimuli, as well as approaches that counteract the immunosuppressive TME, have shown to be key to boost ablation-induced anti-tumor immunity. Recent advances in protein engineering have yielded novel multifunctional antibody formats. These multifunctional antibodies can provide a combination of distinct effector functions or allow for delivery of immunomodulators specifically to the relevant locations, thereby mitigating potential toxic side effects. This review provides an update on immune activation strategies that have been tested to act in concert with tumor debris to achieve in situ cancer vaccination. We further provide a rationale for multifunctional antibody formats to be applied together with in situ ablation to boost anti-tumor immunity for local and systemic tumor control.


Assuntos
Técnicas de Ablação , Imunomodulação/efeitos dos fármacos , Imunomodulação/efeitos da radiação , Neoplasias/imunologia , Neoplasias/terapia , Animais , Apresentação do Antígeno/imunologia , Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/metabolismo , Antígenos de Neoplasias/imunologia , Terapia Combinada , Humanos , Imunossupressão , Imunoterapia/métodos , Neoplasias/patologia , Resultado do Tratamento , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Microambiente Tumoral/efeitos da radiação
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